T h e ketonic fraction (4 g., 40%) was shown t o be 2-ketobicyclo-(2,2,1)-heptane (VI) by its conversion into the 2,4dinitrophenylhydrazone of VI; m.p. and mixed m.p. with an authentic sample was 130-131'. The tertiary amine VI1 ( 3 g., 27% yield) was distilled; b.p. 165-180". Anal. Calcd. for CsH~7X:C, 77.71; H , 12.2. Found: C, 78.21; H, 12.3. The methiodide of this amine melted a t 292" with decomposition. The identity of this product t o that obtained by the reduction of I11 has already been noted. The Hofmann Degradation of the Methiodide of endo-5Dimethylaminobicyclo-(2,2,1)-heptene-2(III).-A solution of the methiodide (5.4 g.) in 100 ml. of 15% potassium hydroxide was distilled in an atmosphere of nitrogen. The exhaust gases were passed through a solution of picric acid. Decomposition occurred when about 85 ml. of water had distilled; however, no trimethylamine was formed. T h e picrate of the product melted a t 190-194" (dec.) and a mixed melting point of this picrate with a n authentic sample of the picrate of endo-5-dimethylaminobicyclo-( 2,2,1)-heptene3 (111), m.p. 190-195' (dec.), was 190-194". A solution of the methiodide (21 9.) in methanol (300 inl.) was treated with silver oxide (9.25 g.), and the solution of methohydroxide was distilled a t atmospheric pressure. The residue decomposed a t 100-180'; however, no trimethylamine was observed. The product was 111. Methylation of &dimethyl-( &phenylisopropyl)-amine ( X ) with formaldehyde and formic acid gave &dimethyl-( phenylisopropyl)-amine ( X I ) , b.p. 68-72' (2.5 mm.), 66% yicld, [ L Y ] ~ f5.11' ~D (absolute ethanol). Anal. Calcd. for C11H17N: C, 80.92; H, 10.50; S , 8.68. Found: C, 81.06; H, 10.59; K, 8.78. Conversion of XI to XI1 was effected by reaction of X I with methyl iodide in ether. The product was recrystallized from ethanol; m.p. 196--197", [ c Y ] * -4.81" ~D (distilled Hzo).
-
a-
!COSTRIBLTION FROM
THE ~ I V I S I O XOF P U R E
Anal. Calcd. for C I ~ H ~ O XC,I : 47.2; H , 6.56. Found: C, 47.6; H , 6.98. Methylation of d-( a-Phenylisopropyl)-amine with Methyl Iodide.-A mixture of 250 ml. of water, 25 g. of sodium carbonate, 11.2 g. of X and 30 g. of methyl iodide was heated a t the reflux temperature for nine hours. The reaction mixture was cooled and the crystals filtered, washed with ether, and dried. The product weighed 18.2 g. (72% yield) and was the methiodide of XI. A sample of the product was recrystallized from ethanol. The m.p. and mixed m.p. with the product described in the preceding experiment was 196197'; [ Y ] ~ ~-4.83' D (distilled H20). The decomposition of bicyclo-(2,2,1)-2-heptene-5 acetate' was carried out by allowing the ester t o pass (25 g./hr.l through a hot tube (580") in an atmosphere of nitrogen. A material balance was not obtained; however, the following products were isolated: ( a ) acetylene (in exhaust gas), ( b ) acetic acid, (c) cyclopentadiene (n1.p. and mixed m.p. of dibromo derivativea was 4546') and (d) vinyl acetate. The Decomposition of the Methyl Xanthogenate of endo5-Hydroxybicyclo-(2,2,1)-heptene-2 (XIIb).-The crude xa~ithogeiiate~ (b.p. 120-126" (10 m m . ) ) was decomposed a t 250' in an atmosphere of nitrogen. A small amount of volatile oil (ca. 5%) boiling a t 40-70' was obtained. This product reacted with phenylazide in ether t o give a crystalline product (dec. 200') which was insoluble in ether, benzene, alcohol and chloroform. The light tan needles werc washed with alcohol and ether. ,1nal. Calcd. for CigHia06: C, 69.08; H, 5.49. Found: C, 69.03; H, 5.81. 17) K. Alder and H. Rickert, ibid., 643, 15 (1939). (8) E. Farmer and W. Scott, J. Chem. Soc., 177 (1029). (9) Whitmore and Simpson, THISJOURNAL, 55, 3809 (1933j.
MINXEAPOLIS 14, MINXESOTA
CHEMISTRY
OF
THEN A r I O S A L KESEARCH COUNCIL
OF
CANADA]
The Characterization of Methyl and Methylene Groups in Steroids by Infrared Spectrometry. I. Correlations of Bending Frequencies with Molecular Structure' BY R . NORMAN JONES
AND
A. R. H. COLE^
RECEIVED APRIL11, 1952 The major absorption bands between 1360 and 1500 cm.-' in the spectra of steroids can be assigned to vibrations of inethyl and methylene groups in the molecule. These vibrations appear to be localized in individual methyl and methylene groups, and the following correlations between molecular structure and infrared spectra have been established for this region of the spectrum. ( a ) The cyclic methylene groups of the steroid ring system absorb a t a different frequency from the linear methylene groups in the side chain. (b) Methylene groups adjacent t o carbonyl groups and t o ethylenic linkages absorb a t characteristic positions. In steroids containing the group -CHz-CO- the frequency of the a-methylene bending vibrations is determined by the location of the carbonyl group and serves t o supplement the C=O stretching frequency for the characterization of the carbonyl position. ( c ) The angular methyl groups, the terminal side chain methyl groups, and the methyl group in the acetoxy radical of steroid acetates, absorb a t different positions and can be distinguished. The band positions associated with these various types of methyl and methylene groups are listed in tables, and examples are given t o illustrate the application of these correlations t o the elucidation of molecular structure.
The infrared absorption bands of large organic molecules may be classified into three principal types; (i) a relatively small number of bands due to stretching vibrations of specific groups, notably 0-H, C-H, C=O, and C=C in the higher frequency region (1575-3650 ern.-'); (ii) C-H bending bands of methyl and methylene groups between 1350 and 1500 cm.-'; (iii) a complicated pattern of overlapping bands due to skeletal stretching vibrations and C-H deformation vibrations below 1350 cm.-I. The latter absorption is most sensible to small changes in molecular structure and
has been aptly described as the "fingerprint" region. An extensive study of the bands due to specific 0-H, C=O and C=C stretching vibrations in steroids has enabled a set of correlations to be established between band position and molecular and these correlations have proved useful in determining the structure of newly isolated steroids. From studies of the infrared spectra of simple ali-
(1) Presented, i n part, a t a Symposium on Molecular Spectroscopy held a t the Ohio S t a t e University, Columbus, Ohio, June, 1950, and published as Contribution No. 2857 from t h e Laboratories iuf T h e S a t i o n a l Research Council of Canada. ( 2 ) National Research' Council Postdoctorate Fellow.
JOUREAI.,
(3) R. N. Joues and K. Dobriner, Vitamiits aitd Hormoses, 7 , 293 (1949). (4) R . N. Jones, P. Humphries, E . Packard a n d K D o b r i n c r , THZS
71, 2 1 1 (1949). I-,r\. 5trtmg a b s o r p t i o n bands between 1 4 7 i i i i i t l 1 i 0 0 c m -1, t h r i t iirr ) r o l J d h i \ diir t u viIJrdtIun\ u f ( h e t,.ii,~rie r i i i g t r u l (1,) ill I i n \ I I ~ C iii t h \ I ilr u i r f h ~ l r u rgroup5
Nov. 20, l!LV
STEROIDS : RENDINGFRRQUENCIRS WITII MOLECULAR STRUCTURE
5659
N
1360
a W a
Fig. 5.-Infrared
WAVE NUMBER CM-'. spectra illustrating absorption characteristic of the acetate group (bands L and N): A, cyclohexanol acetate; B, androstanol-3p acetate; C, androstanoLl7b acetate.
A14-ergostenolwhere the only methylene group adjacent to the double bond is in the 5-membered ring, nor does it occur in AZ2-ergostenederivatives (XII) where there are no a-methylene groups. The same band is observed also in ap-unsaturated ketones, provided the necessary conditions are met. Thus it occurs in A4-3-ketones (XIII) and A1n4-diene-3-ketones(XVI) which have a free methylene group a t c6 but not in Al-3-ketones (XIV) nor in A4s6-diene-3-ketones(XXIII). A band a t 14351440 cm.-' is observed also in the spectra of steroid estrogens and other steroids in which rings A or B are aromatic, and in A4n6- and A5s7-diene~.14 It seems plausible to attribute these bands to the bending vibration of the a-methylene group, perturbed by the adjacent unsaturated linkage, but this interpretation has not yet been checked by observations on suitable deuterated compounds. Applications to Determinations of Structure.The value of this region of the spectrum in the elucidation of molecular structure is potentially considerable, and it is enhanced by the fact that the specific methyl and methylene band positions are retained when two or more functional groups are present. Thus in androstanedione-3,17 bands occur both a t 1408 and 1420 ern.-' characterizing the methylene groups a t C ~ and G a t C2 and C4, respectively. An excellent illustration of the independence of these vibrations is provided by the spectrum of A4-19-norpregnenedione-3,20 (VII) shown in Fig. 6. The six bands which occur between 1350 and 1500 cm.-' are cross referenced by the letters A, C, E, G, K, 0 to the characteristic band positions listed in Table 11. Bands A and C can be assigned to the (14) Aast-Dienes also possess a band at 1428 c m . - l . T h e interpretation of t h e methylene region in t h e spectra of conlogated dienes is
still unclear sqd merits further investigation.
six unperturbed cyclic methylenes a t C1, C,, C11, C12, C14 and (215; band E to the methylene a t Ca adjacent to the A4-double bond; band G to the Cp methylene adjacent to the Cs-carbonyl; band K to the angular methyl group a t CISand band 0 to the Czl-methyl group next to the Czo-carbonyl. From the C=O and C=C stretching regions shown also in Fig. 6 the 20-ketone group, the A4-3-ketonegroup and the A4-doublebond are characterized by the position of bands CY, fl and y. Thus an analysis of these two regions of the spectrum provided a fairly complete interpretation of the whole structure of this steroid. B
I 1750
I I6 50 WAVE
I ,
I
145q NUMBER CM.-.
I 1350
Fig. 6.-Infrared spectrum of A'-19-norpregnenedione3,20: A, C=O and C=C stretching regions; B, methylmethylene bending region; letters on structural formula relate to band assignments (see text).
Fig, 7,-Infrarrti
WAVE NUMBER CM.-'. spectra of cholestanone-:i and cholestanone-7 illustrating t h e t h v mrlxmyl positions
LISC of
11n11ds F nntl G t o differentinte between
Absorption in the methyl-methylene region has B loop also proved useful in determining the location of carbonyl groups in steroids. From observation of the position of C=O stretching bands it is not possible to distinguish unequivocally among steroids containing non-conjugated carbonyl groups a t Cs,C4, Cg, C,,CI1, Clz or Czn, since these groups give C=O stretching bands in overlapping ranges between 1706 and 1719 em.-' in carbon disulfide or carbon tetrachloride s ~ l u t i o n . However, ~~~ the methylene groups a- to the 3-ketone absorb a t 1419 cm.-' and can be easily distinguished from the corresponding band a t 1434 c m - ' in 1,7 , 11 or 12-ketones; an example illustrating this is shown in Fig. 7. I n 20-ketones in which there is a methyl group a t Csl there is the characteristic inethvl ahsorption a t 1336 cm.- '. The necessity of a free a-methylene group for absorption between 1400 and 14i35 c m - ' J K I ~ also be 0 useful in distinguishing among substituted ketoster1450 1350 1500 1400 WAVE NUMBER C M - ' oids. The spectra of A4-2-carbomethoxycholestenone-.? (XXIV) and A4-l-carbomethosycholeste~~- I ig 8 --Infrared 5pectra ~llustratinguse of band G t o one-3 (XXV) are shown in Fig. 8. In X X V which c l i f f ereii t u t c iwt \v c cn h u b s t ituted and 4-whstituted A d - % contains a free inethylme a t C2 the eupcctetl hantl k r t 0 1 1 e\
--
L'
' I
IIICOOC
\fin CH3
"
i
a t 1421 cm.-' is observed, while in XXII' where the carbornethoxy group is introduced at C z this band is missing. Finally, it may also be pointed out that this region of the spectrum can be particularly valuable for distinguishing among steroid homologs containing the saine functional groups. In Fig. 9 are shown the spectra of A22-3-isoergostenol-3a(XXVI) arid A?"~-isostifn3stPnol-.7a (XXVII), two ster-
oids which differ only in the presence of a methyl or an ethyl group a t C&J. In the regions accessible to study tn carbon disulfide solution these curves are nhllCJst identical, and might reasonably be mistaken lor the spectra of the saine compound. In the niethyl bending region the spectra of XXVI arid XXT'I I differ quite significantly, XXVI possessing two resolved maxima and two inflections while XX\'I I powcwes three resolved peaks
CH
1
R
CHJ
/
Nov. 30, 1952
80
STEROIDS '
BESDINCFREQLrFISCIFS WITH ~ ~ O L E C I J L ASTRlTCTTTRF R
.7BG 1
%---
::I 20
L 3600
L
2800
I
I WNE
Fig. 9.-Infmred
I
I I200
1400
I
I 1000
I
I
NUMBER GM:'.
absorption spectra illustrating use of methyl-methylene region t o differentiate between steroid homologs: A, ~**-,7-isoergo~teiioI-~Lu, B,~ 2 2 - . ~ - i s o s t i g m a s t e n o l - 3 ~ .
Discussion of the more general aspects of this investigation will be deferred for consideration in the following paper. Acknowledgments.-During the course of these investigations the authors have enjoyed the opportunity of frequent discussion with the late Dr. Konrad Dobriner of the Sloan-Kettering Institute, New I'ork, and his interest in the work is gratefully aclinowledgetl. l y e wish to thank the several in-
vestigators, listed individually in a footnote to Table I, who made available many of the compounds to us and Dr. B. Kolin who provided the spectra of a number of the steroid acetates and monoketones. Thanks are also due to Miss L. Groth, Mr. D. S. Keir, Mr. R . Lauzon and Mrs. M. MacKenzie for technical assistance in the determination of the spectra. 0 1 1 A W A , CANADA
